Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop breast cancer during their life time. Approximately, 255,180 new cases of breast cancer will be diagnosed in 2017 and 41,070 women will die of the disease. Cancer Care Ontario and ASCO convened a Working Group and Expert Panel and following a systematic review of the literature, developed evidence-based recommendations regarding the use of bisphosphonates and other bone-modifying agents, as adjuvant therapy, for patients with breast cancer. These guidelines are based on several important findings noted in previously published studies and in the more recently published Oxford Overview (Early Breast Cancer Trialists’ Collaborative Group) analysis of individual patient data.

1) Adjuvant bisphosphonates were found to reduce bone recurrence and improve survival in postmenopausal patients with non-metastatic breast cancer (including those with natural menopause or menopause induced by ovarian suppression or ablation)

2) The absolute benefit with adjuvant bisphosphonates was greater in patients who were at a higher risk of recurrence, and almost all clinical trials were conducted in patients who also received systemic therapy.

3) Most studies evaluated ZOMETA® (Zoledronic acid) or BONEFOS® (Clodronate), and there was extremely limited data for other bisphosphonates. Although XGEVA® (Denosumab) was found to reduce fractures, long-term survival data is awaited.

The following is a summary of the panel’s recommendations:

Recommendation 1

a) Administration of bisphosphonates as adjuvant therapy should be considered for postmenopausal patients with breast cancer (including patients who are premenopausal before treatment and have menopause induced by ovarian suppression as detailed in Recommendation 5) deemed candidates for adjuvant systemic therapy.

b) The final decision of whether or not to administer bisphosphonates should be made during consultation between the patient and oncologist, taking into account patient and disease characteristics, including the risk of recurrence, and weighing the potential benefits and risks.

Recommendation 2

a) Zoledronic acid and Clodronate are the recommended bisphosphonates for adjuvant therapy in breast cancer.

b) There is a need for more information comparing different agents and schedules, and it is recommended that such trials be conducted to establish the utility and optimal administration of other bisphosphonates for adjuvant therapy.

Recommendation 3

a) There is insufficient evidence at this time to make any recommendation regarding the use of Denosumab in the adjuvant setting.

b) It is recommended that studies directly comparing Denosumab with bisphosphonates and evaluating administration schedules, be conducted.

Recommendation 4

a) For patients who will receive adjuvant bisphosphonates (Recommendation 1), Zoledronic acid 4 mg IV over 15 minutes (or longer) every 6 months for 3 to 5 years or Clodronate PO 1,600 mg daily for 2 to 3 years is recommended. Different durations may be considered.

b) More research is recommended comparing different bone-modifying agents, doses, dosing intervals, and durations.

Recommendation 5

For purposes of adjuvant bisphosphonate use, the definition of menopause should include natural menopause (at least 12 months of amenorrhea prior to initiation of chemotherapy or endocrine therapy) and menopause induced by ovarian ablation or suppression (but not the cessation of menses due to chemotherapy alone). In women aged 60 years or less with a previous hysterectomy and ovaries left in place, Luteinizing Hormone, Follicle Stimulating Hormone and Serum Estradiol should be in the postmenopausal range and measured prior to initiation of any systemic therapy, to receive adjuvant bisphosphonates.

Recommendation 6

a) A dental assessment is recommended prior to commencement of bisphosphonates, where feasible, and any pending dental or oral health problems should be dealt with prior to starting treatment, if possible. Patients should be informed of the risk of developing osteonecrosis of the jaw, especially with tooth extractions and other invasive dental procedures. Patients should inform their dental practitioner of their treatment. Patients with suspected osteonecrosis of the jaw should be referred to a dental practitioner with expertise in treating this condition. Recent guidelines or position papers by groups such as the International Task Force on Osteonecrosis of the Jaw, the American Association of Oral and Maxillofacial Surgeons, and the American Dental Association should be consulted.

b) Patients should have Serum Calcium measured prior to starting treatment. Patients receiving intravenous bisphosphonates (Zoledronic acid) should be monitored for renal function, prior to starting this treatment and for Serum Calcium and increase in Serum Creatinine, throughout the treatment period.

c) Calcium and vitamin D supplementation is recommended unless otherwise contraindicated. Oral bisphosphonates and Calcium should not be taken concurrently. Several monographs suggest an interval of at least 2 hours to allow for maximum absorption.

d) Symptoms such as ocular pain or loss of vision may be due to serious inflammatory conditions such as uveitis or scleritis and should be promptly evaluated by an ophthalmologist.

Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. Dhesy-Thind S, Fletcher GG, Blanchette PS, et al. DOI: 10.1200/JCO.2016.70.7257 Journal of Clinical Oncology – published online before print March 6, 2017